Synthesis of Selenoaziridines: A Study on Stereochemical Outcomes of the Reaction of Aziridine Radicals and Anions Generated from Iodoaziridines.

The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C-I bond using alkoxides as a source of single electrons. These form predominantly trans-substituted selenoaziridines dependent on the size of the diselenide. cis-Aziridinyllithiums generated by Li-I exchange also react with diselenides stereospecifically to form a range of cis-selenoaziridines. Proposals for the stereochemical outcome are presented.

Synthesis and purification of iodoaziridines involving quantitative selection of the optimal stationary phase for chromatography.

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °C in the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 °C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control. Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by (1)H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by (1)H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity.

Stereospecific functionalization of iodoaziridines via unstabilized aziridinyllithiums generated by iodine-lithium exchange.

Lithium-iodine exchange on alkyl- or aryl-substituted N-tosyliodoaziridines afforded unstabilized aziridinyllithiums, which were subsequently trapped at low temperatures with a range of carbon and heteroatom electrophiles affording cis-substituted aziridines exclusively. When using isocyanates as electrophiles, access to aziridine carboxamides or 1,3,5-trisubstituted hydantoins can be selected by control of reaction temperature.

Synthesis of cis-C-iodo-N-tosyl-aziridines using diiodomethyllithium: reaction optimization, product scope and stability, and a protocol for selection of stationary phase for chromatography.

The preparation of C-iodo-N-Ts-aziridines with excellent cis-diastereoselectivity has been achieved in high yields by the addition of diiodomethyllithium to N-tosylimines and N-tosylimine-HSO2Tol adducts. This addition-cyclization protocol successfully provided a wide range of cis-iodoaziridines, including the first examples of alkyl-substituted iodoaziridines, with the reaction tolerating both aryl imines and alkyl imines. An ortho-chlorophenyl imine afforded a ß-amino gem-diiodide under the optimized reaction conditions due to a postulated coordinated intermediate preventing cyclization. An effective protocol to assess the stability of the sensitive iodoaziridine functional group to chromatography was also developed. As a result of the judicious choice of stationary phase, the iodoaziridines could be purified by column chromatography; the use of deactivated basic alumina (activity IV) afforded high yield and purity. Rearrangements of electron-rich aryl-iodoaziridines have been promoted, selectively affording either novel α-iodo-N-Ts-imines or α-iodo-aldehydes in high yield.

Palladium-catalyzed cross-coupling of aziridinylmetal species, generated by sulfinyl-magnesium exchange, with aryl bromides: reaction optimization, scope, and kinetic investigations.

A series of novel, highly substituted N-PMP aziridines have been accessed in high yields by palladium-catalyzed cross-coupling of intact aziridines. The cross-coupling employed aryl bromides and tertiary organometallic aziridines, generated from sulfinylaziridines by sulfinyl-magnesium exchange and transmetalation to the aziridinylzinc with zinc chloride. A wide range of electron-rich and electron-poor aryl bromides were utilized to afford the functionalized aziridine products as single diastereoisomers with retention of configuration at the reacting center. Assessment of the reaction kinetics showed zero-order in both the aziridine species and the aryl bromide. This indicated that the rate-determining step was reductive elimination from the palladium(II) species bearing both the aziridine and aryl groups to form the hindered C-C bond. The intermediate aziridinylzinc species underwent a progressive, background degradation that led to a plateau in yield and afforded reduced yields in substrates with ortho-substituted aryl groups, which are less reactive due to the additional steric demands.

Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium and in situ generated N-Boc-imines.

The first preparation of iodoaziridines is described. The addition of diiodomethyllithium to N-Boc-imines affords these novel aziridines in high yields. The reaction proceeds in one-pot via a highly diastereoselective cyclisation of an amino gem-diiodide intermediate.